That "D" Peter Agre '74 (MD) got in chemistry his senior
year at Roosevelt High School in Minneapolis — you
know, the "D" he loves to bring up when he's expected to
say something self-congratulatory about his 2003 Nobel
Prize in chemistry for the discovery of aquaporins —
he didn't get it for being dumb.

There he is in his high school yearbook — the lanky
towheaded kid with the mischievous smile — member of
the yearbook staff and the cross country ski team, Mr. Most
Likely to Succeed. Agre, the Johns Hopkins professor of
biological
chemistry who won the Nobel for his discovery of the
proteins that form the channels that transport water
through cell membranes, credits his father, a college
chemistry professor, with sparking his interest in science.
He mentions two-time Nobel winner Linus Pauling, who stayed
at his family's house once, as an inspiration, too. But
high school chemistry just wasn't as exciting to Agre as
The Substandard, the underground newspaper he and
some friends started their senior year.

"He was probably really brilliant, but he really didn't
apply himself," says James L. Thornton Jr., Agre's high
school chemistry teacher, now 74. "He did the labs, but he
never wrote them up. Peter was just a typical young guy who
goofed off."

"I was impossible," says Agre, who dropped out of high
school the later part of his senior year but has since then
become a champion of the teachers who inspire children to
learn about science. He laughs, slightly embarrassed at the
thought of his young, rebellious self. "It was just boring
high school chemistry, but I used it as an opportunity to
act out."

Other people might hide the "D," bury it among past
transgressions. Agre seems to revel in it. Owning up to the
dismal chemistry grade establishes the 55-year-old
scientist and internist as an ironic guy who doesn't mind
poking fun at himself. It also serves as a reminder that
when it comes to science, hard work, curiosity, and luck
are as important as class rank, credentials from fancy
schools, and honor rolls.

Maybe even more important.

"There are a lot of prima donnas in science," says Don
Coffey, a professor in the
Department of
Urology who met Agre when Agre was a student at Hopkins
School
of Medicine in the early 1970s and has become one of
his trusted advisers. "Then you see Peter, who is an
honest, humble, enthusiastic man. In telling you about the
"D", he's trying to tell you, you don't have to be Phi Beta
Kappa or go to Harvard. You just have to be motivated,
dedicated, and work hard, and you can do it."

Somewhere in between earning that infamous "D" and winning
the Nobel Prize, Peter Agre came to see science not as a
competition or a politically tinged academic endeavor but
as a series of turns in the river that deserve to be
followed. And he came to see himself as Huckleberry
Finn.

"Science should be an adventure," Agre says. "It should be
so exciting that you wake up at night and you want to go
back to the lab not because, 'God, if I get eight more
papers then I'll be promoted and we'll beat our
competitor,' but because it's fun. Huck was unafraid to go
his own direction, and there's a level of him that probably
applies to me. That's why I couldn't concentrate in high
school."

Peter Agre was voted "Most Likely to Succeed" in high
school, even though he got a "D" in chemistry.

Aquaporins are no run-of-the-mill discovery. These "water
pores" are the key to the movement of water in and out of
all human cells.

"A lot of the basic physiological processes that we all
know about involve fluid transport," Agre says —
processes like sweating, urinating, swelling, crying. Says
Agre, "Aquaporins aren't important because they're the cure
to cancer, but they are the answer to some of life's
persistent questions."

"How can our kidneys concentrate urine so when we go out on
a hot day we don't die of dehydration?" he asks. The
answer: aquaporins. "How does an individual respond to
starvation? Fat is stored in fat cells as triglycerides.
How does it get out? It gets out through aquaporin
secretion."

At the Nobel Prize ceremony in Stockholm in December 2003,
Bengt Norden, chairman of the Nobel committee for
chemistry, said Agre's discovery was intimately connected
with the question, What is life? He added that the water
channels were "a decisive discovery that opened the door to
a whole series of biological, physiological, and genetic
studies of water channels in bacteria, mammals, and
plants."

Scientists had spent years looking for the water channels.
Agre stumbled upon them while working on an unrelated
project, and then threw himself into figuring out what they
were and how they worked.

In the late 1980s, Agre, then a Hopkins specialist in blood
disorders, was researching Rh incompatibility in pregnancy.
One day, as he and his colleagues in the lab purified the
Rh protein they needed, they noticed a "contaminant," a
different protein found in blood cells. The protein was
abundant and looked like proteins found in the human kidney
and in plants. Intrigued, Agre decided to try to find out
what it was.

"Most people would have discarded it as unrelated to what
they were after," says Paul S. Lietman, professor of
medicine at
the John Hopkins School of Medicine. "He had the foresight
to realize that what he stumbled onto was bigger than what
he had set out to do."

"Imagine you are driving through Western Maryland and you
come upon a town of 200,000 people that's not on any map,"
Agre explains. "That's what it was like."

Agre's office wall pays homage to some of the important
people
in his life: his children, his father, Nobel laureate Linus
Pauling, and John Parker, who suggested that Agre had
discovered the elusive water channel.

Finding the channels wasn't enough, however. Agre wanted to
see how they worked. "Most scientists did not believe water
channels existed, since no one could isolate them," he
says. A few scientists predicted that water channels
existed, but no one knew for sure. "Having a great idea is
wonderful," Agre says. "You have to actually prove that
it's correct."

When John Parker, Agre's friend and former attending
physician at University of North Carolina at Chapel Hill,
suggested that this new protein could be a channel for
water, Agre and William Guggino, Hopkins professor of
physiology and
pediatrics,
worked out an elegant experiment to test his theory. In
October 1991, Agre's lab cloned the DNA encoding the
protein they had discovered and injected the corresponding
RNA into six frog eggs. Test eggs injected with
complementary RNA produced the new protein and became water
permeable. In fresh water, they swelled and burst. Control
eggs not injected with RNA failed to swell. The
investigators performed many other experiments and checked
many control conditions; every determination indicated that
the new protein is a channel permeated only by water. They
had found the elusive water channel. News of their
discovery spread throughout the scientific community.

"Hokey smoke!" Agre says of the experiment. "People called
us up within days. Scientists had been committed to solving
the water transport problem."

Hanging on the wall of Agre's messy shoebox of an office is
a photo of these exploding frog eggs — a series of
fuzzy orange circles that look more like pieces of abstract
expressionism than a career-making discovery. Since that
experiment, 10 aquaporins have been identified in human
cells. Present in such places as the blood, the kidneys,
and the brain, aquaporins help regulate the balance of
water inside cells.

While the egg pictures serve as a reminder of what he's
done, other photographs hanging nearby tell more about who
he is. Parker, the UNC doctor whose suggestion led Agre to
his discovery and who died in 1993, is memorialized on his
wall.

Above that photograph are portraits of his four children,
Sara, 25, Claire, 23, Clarke, 18, and Anne, 14. Agre and
his wife, Mary, a preschool teacher, have been married for
29 years. Even though his research has resulted in six-day
workweeks and lots of travel, he's found time to be
involved with his children's activities both as a
recreation league soccer coach and as an assistant
scoutmaster for Boy Scout Troop 35.

"One of Peter's major assets as a scientist is a
willingness to do things other scientists wouldn't do,"
says Vann Bennett, Agre's former Hopkins
roommate.

"You do whatever you have to do," Agre says of balancing
work and home life. He used to block out his schedule eight
months in advance to ensure he'd be able to take his Scout
troop on two-week trips backpacking in the Rocky Mountains
or canoeing in the Canadian wilderness. As is typical with
him, he makes sure to share the credit. "My wife does all
of the hunting and gathering," he says. "She covers for
me."

He loves to tell the story about how on the day he learned
he won the Nobel, his daughter Anne returned home from high
school and pronounced her father's Nobel "cool." His
mother, two brothers, children, and wife all accompanied
him to Stockholm for the award ceremony.

"Tell him not to let it go to his head," Agre's mother,
Ellen, said to Mary when she learned her son had won the
Nobel. There's little worry of that. "The children are not
going to let that happen," Mary says.

Next on the wall hangs a black-and-white portrait of his
father, Courtland Agre, taken when he was about 35 years
old and working as a chemistry professor at St. Olaf
College in Minnesota. Agre remembers his father, who died
in 1995, as optimistic and filled with ideas. "He was never
down," Agre says, surveying the image of the smallish man
with the wavy red hair. "He was always looking forward, but
in some ways with a lack of quality control with regard to
some of his inventions." For instance, says Agre, his
father invented a substance that could be used to
strengthen shoe soles. Not feeling the need to refine the
product further, he put it on the shoes of his five
children. The soles left black scuff marks on all the
floors. "Ninety percent was good enough," Agre recalls.

Courtland Agre served on the American Chemical Society's
education committee with Linus Pauling. When Agre was 14,
Pauling, who had just won the 1962 Nobel Peace Prize for
initiating the Nuclear Test Ban Treaty, came to speak in
Minnesota and stayed with the Agre family. Meeting Pauling
made a big impression on Peter, who has hung his father's
signed photograph of Pauling in his office, just under the
picture of his dad.

Pauling "had a humorous way of connecting with people,"
Agre says. "It was an inspiration."

Agre tells the story of how Pauling, who was invited to a
reception for American Nobel winners by President John F.
Kennedy in 1962, used the invitation as an opportunity to
take part in a demonstration outside the White House to
protest U.S. atmospheric nuclear tests. "That evening at
the White House, [Pauling] went through the receiving line
and he came up to President and Mrs. Kennedy, and Kennedy
turned to him and said, 'Dr. Pauling, I understand you've
been around here earlier today.'"

Agre giggles at the thought. "Could you imagine Bush doing
that?" he says. "[Pauling] would have been dragged
away."

Agre's father encouraged his oldest son to become a doctor.
And, after dropping out of high school, getting his diploma
through night school, and delivering war materiel by truck
for a few months, Agre went to Augsburg College in
Minnesota and graduated in three years with a degree in
chemistry.

Since Agre's discovery, studies have linked aquaporins
to the maintenance of the blood-brain barrier; to the
functioning of salivary and tear glands; and to the
transportation of water in skeletal muscles, lung cells,
and kidney cells.

With characteristic humility, Agre downplays his acceptance
to Hopkins' School of Medicine. He told The Baltimore
Sun he was admitted "on the Norwegian-from-Minnesota
quota" and goes so far as to say that he and Hopkins cancer
researcher Bert Vogelstein, both of whom graduated from
Hopkins in 1974, claim to be the worst student in their
class.

Former classmates and professors remember Agre as an
intelligent, enthusiastic student. After graduation, Agre
planned on practicing medicine, but when he encountered the
lab where his roommate Vann Bennett was working, he became
interested in research, too. The third floor lab in the
Basic Science Building, run by Pedro Cuatrecasas, was a
vibrant, dynamic place inhabited by a Spanish
revolutionary, a Palestinian refugee, a Conservative Jew,
and an Italian actor. They all became close friends.

"It was the people there who engaged me as much as the
science," remembers Agre. "It was just scintillating."

Agre, who had an interest in international health, decided
that he wanted to purify the E.coli bacteria that caused
"traveler's diarrhea" and that the Cuatrecasas lab was the
place to do it. He never asked permission — he just
moved in and started working.

"The lab was big enough. Pedro didn't seem to mind," says
Bennett '74 (MD), '76 (PhD), now the James B. Duke
Professor of cell biology at Duke University Medical Center
and an investigator with the Howard Hughes Medical
Institute. "I just moved over and gave him some bench
space."

Driven but "disorganized," as Agre describes himself, he
never published the results of his research from his
postdoctoral fellowship in the Cuatrecasas lab. After
graduation from Hopkins he completed an internship and
residency at Case Western Reserve University in Cleveland
and a postdoctoral fellowship in hematology at the
University of North Carolina at Chapel Hill.

Agre received his award in Stockholm, Sweden, from King
Gustav.

Agre returned to Hopkins in 1981 — not for some
tenure-track professorship but as a research associate in
the department of cell biology. He was working with
Bennett, who had just moved his small lab from Burroughs
Wellcome to Hopkins. To some, Agre's move looked like a
step back.

"Peter came to Hopkins with no faculty guarantees... no
guarantees this would lead to anything at all," says
Bennett, adding that Agre wrote a clinical investigator
grant to return to Baltimore. "While he was in the lab he
learned a lot of red cell membrane biochemistry, which was
helpful to him later, but it was a risky move. Here Peter
sells his house in Chapel Hill and takes his family on a
salary of $25,000 and moves back to Baltimore where the
rest of his classmates were in private practice. Very few
people would have done that, and if they had, most of them
would have been terrified."

Agre, who has biked from Minneapolis to Baltimore and
traveled the world alone, was too adventurous to stay put
in North Carolina, Bennett says. "One of Peter's major
assets as a scientist is a willingness to do things other
scientists wouldn't do," Bennett says. "He combined this
with real focus and dedication and super science, and the
combination is lethal, in a good way."

For Agre the move seemed like a practical way to get more
training. "Drug companies are a lot less exciting than
universities," says Agre, who, during his first few years
in Baltimore, moonlighted as the fight doctor at the
Steelworkers Hall boxing matches in Dundalk. "It was no
sure thing at Hopkins. It just seemed like we'd come up for
three years, get some training, and move back to Chapel
Hill."

Within three years Agre was a Hopkins assistant professor
in the departments of medicine and cell biology. He worked
in hematology and saw patients while doing research.

In 1993 when Hopkins started a new graduate program in
cellular and molecular medicine, Agre moved between
medicine and science, doing more research on aquaporins and
the role they played in various diseases. "I felt like a
kid in a candy store," Agre says. "You know, most people
don't have the opportunity to go to work and have a lot of
fun. But I always like to go to work. It's not like I have
a sad home life. I have a lovely wife. The house is kind of
beat up because we have four kids and the dog chews the
shutters off, but it's a wonderful life."

After Agre's lab figured out how aquaporins worked, he
didn't expand into a mega-lab filled with dozens of
scientists or apply for huge grants so that he could
systematically knock out every aquaporin in a mouse model.
He didn't become hyper-competitive and secretive about his
work. Instead, he reminded the dozen or so people in his
lab to focus on experiments no one else is doing and not to
worry about experiments that anybody could do. Agre told
his lab to steer clear of the mundane.

"It looked like this was going to be very interesting,"
Agre says. "Everyone worked on aquaporins answering
questions like, How are they regulated? How many related
aquaporins are there? How are they expressed? and Which
diseases are they involved in?"

Agre says he knew the field of study was going to
"mushroom." It did. Over the next several years there were
some 1,000 papers published on aquaporins. Since the frog
egg experiment in 1991, studies have linked water channels
to the maintenance of the blood-brain barrier; to the
functioning of salivary and tear glands; and to the
transportation of water in skeletal muscles, lung cells,
and kidney cells. Scientists in Agre's lab are continuing
to look at aquaporins' role in human diseases like malaria,
brain edema, and osteoporosis.

Agre took his two minutes in the spotlight to recognize
the "heroes behind past, present, and future Nobel Prizes
— the men and women who teach science to children in
our schools."

Agre avoids direct scientific competition and encourages
collaboration. His lab has worked on aquaporins with half a
dozen Hopkins labs, as well as a dozen labs in Denmark,
Norway, Switzerland, and Japan. "Science is a social
endeavor," Agre says. "Scientists who don't interact with
other scientists are less likely to succeed in their
work."

And scientists who rush their work to try to be first
invariably make mistakes. "'A researcher is just like a
pilot,' Peter says," recounts Masato Yasui, assistant
professor of pediatrics and a researcher in the Agre lab.
"Even a single mistake shouldn't be allowed."

But not all of Agre's lessons are so easy for the less
senior members of the lab to accept. Graduate student Dan
Gorelick-Feldman used to complain to Agre when a competitor
would do something Gorelick-Feldman thought their lab
should have done. Agre's response was always the same.
"Don't worry about it — they're doing our work for
us," he'd say. Or maybe, "Science is a marathon, not a
sprint."

"He's always telling me not to worry about what anyone else
is doing," Gorelick-Feldman says. "Even if someone else
beats you, sooner or later they're going to make a
mistake."

And then there's his usual response to a paper about a
ho-hum result for a middle-of-the-road scientific journal.
Agre doesn't criticize it or the writer. Instead, with tact
and civility, he pronounces it "a scholarly work."

"I'm going to use that one when I'm a professor,"
Gorelick-Feldman says smiling. "A scholarly work."

Agre's greatest strength as a mentor is that he is
interested in the lives of his junior colleagues both
inside and outside the lab, now and later, says Landon
King. A Hopkins associate professor of medicine and
biological chemistry, King has been working with Agre in
the lab since 1993. "Peter addresses not just the issues
you're facing in the lab day to day but how one puts the
pieces together to form a career," he says. "He helps you
see what you should be thinking about in a year from
now."

In the months since the Nobel Prizes were first announced,
Agre — who shared the prize with Roderick MacKinnon
of Rockefeller University — has been launched into
the world of scientific celebrity. At the awards ceremony
in Stockholm, he found himself swarmed by scientists who
wanted to know more about aquaporins and their role in
everything from cataracts to kidney disorders. His calendar
of speaking engagements is booked through this year and
quickly filling up for 2005. And he's still trying to
figure out how to begin responding to the 1,872 e-mails and
thousands of invitations, congratulations, and requests for
autographs he's received.

"They don't want me, they want some Nobel Prize guy," Agre
deadpans while sitting at his desk a few feet away from the
piles and cardboard boxes of letters that threaten to
overtake his office.

Over the last six months Agre hasn't just been fielding
inquiries, he's been figuring out ways to use his fame for
a larger cause. Always willing to speak his mind, he used
his stature as a Nobel Prize winner to protest the
prosecution of scientist Thomas Butler of Texas Tech
University. Butler, a respected plague researcher and
former Hopkins clinical fellow in infectious diseases,
faced felony charges for allegedly mishandling plague
bacteria. He was convicted on 47 of 69 counts by a federal
jury in December 2003.

William Guggino worked with Agre to develop the elegant
frog-egg experiment.

"This is a gross miscarriage of justice," says Agre, who
told The Baltimore Sun he wanted to use part of his
$700,000 in Nobel winnings to help pay for Butler's
defense. "I'm relieved that Dr. Butler was acquitted of all
the serious charges, but he still faces three felony
charges that include wire fraud and theft. Butler is the
world's leading expert on plague. Š There are hundreds,
thousands of poor people in the world dying of this. It's
going to be a grave mistake if they put Tom Butler in
prison." (Indeed, at press time, Butler was sentenced to
two years in prison and fined $15,000.)

And then there's his mission of getting the world to
appreciate science teachers. At the banquet speeches in
Stockholm, other Nobel laureates talked about their
families, their coworkers, and themselves. Agre took his
two minutes in the international spotlight to ask the 1,300
dignitaries and their guests to recognize not the laureates
but the "heroes behind past, present, and future Nobel
Prizes — the men and women who teach science to
children in our schools."

The speech received cheers from the crowd and a thumbs-up
from the prime minister of Sweden, not to mention letters
from science teachers asking him to come speak to their
schools. Agre says he wasn't trying to be politically
correct. "I just thought that was a point I could make
where somebody might listen," he says. "What is it that is
different about us now than our progenitors in the 14th
century? They had Icelandic sagas and Homeric legends that
show us that minds were keen in ancient times. Science is
what's different. The technology that it has produced with
antibiotics and electronics and architecture — this
is where we are different. Science teachers are the ones
who convey this to the young people. And if a young person
connects with science, we've got another 70 years of
productivity from them."

In February, Agre went back to Theodore Roosevelt High
School in Minneapolis to talk to students about careers in
science. It was the first time he had been in one of his
old high school classrooms since he dropped out 37 years
ago. His first message: "If you don't get into a good
college, you won't be a failure," he says, chuckling. His
second: "Learning is fun and exciting and the answers are
not always known."